The technical field of the present invention is tissue engineering, in particular, the construction of tissue engineered female reproductive organs. The invention is particularly useful in constructing tissue engineered vagina, fallopian tubes, uterus, and cervix.
A variety of pathological disorders exist, affecting the external genitalia and mandating extensive surgical intervention (Hendren, H. W. (1998). Cloacal malformations. In “Campbell's Urology” 7th ed., Saunders, Philadelphia, 1991-2001). Male genital reconstruction affords the most currently reported long term clinical success with tissue engineering applications and substantiated suitability for urethral reconstruction (Atala et al. J. Urol. 162: 1148-1151 (1999); Chen et al. World J. Urol. 18(1) 67-70 (2000)). Certainly other disorders like cloacal malformations and exstrophy can result in severe genital ambiguity for both male and females. However, there is a paucity of information regarding the reconstruction of female genitalia and vaginal reconstruction.
Congenital malformations of the vagina, cervix, and uterus have profound implications for gynecological patients. These anomalies are often detected in the adolescent period. For proper management, the physician requires a thorough understanding of normal embryology and sexual differentiation. Although clinical experience helps the gynecologist appreciate the disturbed anatomic configurations, each individual who presents with a defect must be thoroughly evaluated because genital tract aberrations do not necessarily follow any defined and consistent pattern. Examples of female genital abnormalities include ambiguous genitalia, vaginal and uterine atresia, obstructed outflow tract disorders, cervical atresia, urogenital sinus disorders, and virilization disorders (Edmonds, D. K., Obstet Gynecol Clin North Am 27(1):49-62 (2000)). Genital malformations can be particularly disturbing to the patient and her family because they not only have reproductive implications but also significant psychological and sexual overtones that need to be addressed and dealt with in a sensitive and reassuring manner. A more in depth discussion can be found in the textbooks (Rock J A “Surgery for anomalies of the mullerian ducts.” In: Te Linde's Operative Gynecology (8th ed). Edited by J Rock, J. Thompson. Philadelphia, Lippincott-Raven, 1997; Edmonds D K: “Sexual development anomalies and their construction: upper and lower tracts.” In: Pediatric and Adolescent Gynecology. Edited by J Sanfilippo, D Muram, P Lee, J Dewhurst. Philadelphia, W. B. Saunders, 1994; Jones H W Jr: “Construction of congenital uterovaginal anomalies.” In: Female Reproductive Surgery. Edited by J Rock, A Murphy, H W Jones Jr. Baltimore, Williams & Wilkins, 1992).
Congenital and acquired uterine malformations, such as hypoplastic or aplastic uterine anomalies, tumor, trauma, and severe inflammatory diseases, account for a large percentage of female infertility. The options available for uterine reconstruction are limited. Pregnancy cannot be achieved if extrauterine tissues are used for reconstruction. Uterine tissue substitution has been tried experimentally using synthetic biomaterials, however, these attempts have not been successful, likely due to the complex physical and functional characteristics of the uterus (Jonkman et al. Artif Organs, 10: 475-80, 1986)).
Congenital female genital anomalies and cloacal malformations, such as icornuate/septate uterus, uterus didelphys, cervical and vaginal atresia, obstructed genital tract, may also require extensive surgical construction. Surgical challenges are often encountered due to the limited amount of native tissue available. Currently, non-reproductive tract tissues are being used for vaginal construction, despite a number of associated complications. These include treatment such as the transabdominal method of retroperitoneal sacropexy for the creation of sigmoid vagina, for example in a patient suffering from Mayer-Rokitansky-Kuster-Hauser syndrome. These creations however are prone to prolapse, resulting in a “falling-out” sensation in the vagina, pain, leukorrhea and dyspareunia, and necessitating repair. Other patients with, for example, agenesis of the vagina and cervix, but with a functional endometrium, are typically treated by the traditional treatment of hysterectomy with the subsequent construction of a neovagina. This requires a vaginal skin graft that may not heal well, and may also result in disturbances of menstruation.
Currently, the various procedures used for female reproductive organ reconstruction employ non-homologous tissue sources. However, the use of non-homologous tissue for female organ reconstruction is associated with limited functionality. Thus, there is a need in the art regarding the engineering of female reproductive and genital tissues that address the problems these problems.
Accordingly, a need exists for the generation of female reproductive organs using the autologous cells to produce reproductive tract organs and tissues.